Method and compositions for inducing antiarrhythmic activity in animals



United States Patent. 01 ifice 3,475,538 Patented Oct. 28, 1969 US. Cl.424-258 6 Claims ABSTRACT OF THE DISCLOSURE Disclosed are 5,6,7 or=8-hydroxy-2-alkyl-l,2,3,4-tetrahydroisoquinolines; 5,6,7 or8-hydroxy-2-alkyl decahydroisoquinolines; bis-(Z-alkyldecahydroisoquinolines) and esters, acid addition salts and quaternaryammonium salts thereof. The compounds have biological activity inanimals. Some increase arterial blood flow. Others induce antiarrhythmicactivity in animals, especially -(3,4,5- trimethoxybenzoyloxy)-2-ethyldecahydroisoquinoline.

wherein R is a lower alkyl such as methyl, ethyl and propyl, and estersand salts thereof, and novel 5,6,7 or8-hydroxy-Z-R-decahydroisoquinolines of the formula wherein R ishydrogen or a lower alkyl such as methyl, ethyl and propyl, and estersand salts of such compounds, as well as his ethers thereof of theformula wherein R is a lower alkyl such as methyl, ethyl and propyl.

The starting materials used in practicing this invention are the known5,6,7 or S-hydroxyisoquinolines with the commercially availableS-hydroxyisoquinoline being most suitable.

i The novel 5,6,7 or 8-hydroxy-2-R-1,2,3,4-tetrahydroisoquinolines whereR is a lower alkyl can be produced by catalytic hydrogenation, usingmoderate conditions, of the hydroxy-2-lower alkyl isoquinolinequaternary salt. This process can be represented as follows:

wherein R is lower alkyl and X is an anion such as the chloride orbromide ion.

The quaternary salts of the hydroxyisoquinolines can be producedconveniently by reaction of a 5,6,7 or 8-hydroxyisoquinoline with analkyl halide. Alkyl halides such as methyl chloride, ethyl bromide andpropyl bromide may be used in the reaction. The reaction is readilyeffected by combining the hydroxyisoquinoline and alkyl halide in asuitable liquid reaction medium such as a lower alcohol and particularlyethanol. The reaction mixture can be heated, such as at reflux, topromote the reaction. The desired product can then be recovered from thereaction mixture by conventional isolation techniques.

Reduction of the 5,6,7 or S-hydroxy-2-lower alkyl isoquinolinium halideusing moderate catalytic hydrogenation procedures gives the desired5,6,7 or 8-hydroxy-2- lower alkyl-1,2,3,4-tetrahydroisoquinoline in theform of a hydrohalide salt which upon treatment with a base such assodium hydroxide yields the free tertiary amine.

This reduction is conveniently elfected using hydrogen at a moderatelyelevated pressure, such as about 25 to p.s.i., a finely divided platinumoxide catalyst and room temperature. To facilitate the reduction theisoquinoline compound is first dispersed in a suitable organic liquidand advisably one in which the isoquinoline salt is soluble. Ethanol isa particularly suitable solvent for the halide salts. The progress ofthe reduction can be followed by the hydrogen uptake. Once thetheoretical amount of hydrogen has been consumed the reduction can beterminated, the mixture filtered and the filtrate concentrated tocrystallize the desired product as the hydrohalide salt.

Some of the 2-alkyl tetrahydroisoquinolines which may be produced asdescribed are 5-hydroxy-2-methyl-1,2,3,4-tetrahydroisoquinoline,5-hydroxy-2-ethyl-l,2,3,4-tetrahydroisoquinoline,S-hydroxy-Z-propyl-1,2,3,4-tetrahydroisoquinoline,7-hydroxy-2-ethyl-l,2,3,4-tetrahydroisoquinoline, and6-hydroxy-2-butyl-1,2,3,4-tetrahydroisoquinoline.

Although it appeared feasible to effect direct decahydrogenation of the5, 6, 7 or 8-hydroxy-2-lower alkyl isoquinolinium halides to produce the5, 6, 7 or 8-hydroxy-2- lower alkyl decahydroisoquinolines thisreduction, which employs stringent conditions, lead to a bis-(2-loweralkyl decahydroisoquinoline) ether rather than the alcohol. This processcan be represented as follows:

N-Ra-HX -HO O N-Rr [H] N-Ra-HX wherein R is a lower alkyl and X is ahalide ion, and advisably the bromide ion. This reductive condensationcan be effected in glacial acetic acid containing a small amount of astrong acid, and particularly sulfuric acid, using an Adams platinumoxide catalyst and hydrogen at about 25 to 100 p.s.i. The hydrogenationproceeds at room temperature and is usually completed in about 5 to 48hours.

3 After filtering, the filtrate can be made alkaline and the free baseextracted with ether.

Similar ethers may be produced as described in the procedure forbis-(2-ethyldecahydroisoquinoline ether.

The free base of the ether can then be converted to an acid additionsalt such as a hydrohalide or sulfate by conventional procedures or, ifdesired, quaternary ammonium salts can be formed, such as by reactingthe free base with an alkyl halide, alkyl sulfate, aralkyl halide oraralkyl sulfate including methyl chloride, ethyl iodide, ethyl bromideand benzyl chloride.

The unexpectedness of the production of the described ethers is shown bythe application of the same process conditions to the tertiaryhydroxyisoquinolines. The tertiary amines, as the free bases, arereduced to hydroxy decahydroisoquinolines by hydrogenation in glacialacetic acid using platinum oxide as the catalyst. The process can berepresented as follows:

HO HO N [H] N--H Some of the compounds which may be produced asdescribed are S-hydroxy decahydroisoquinoline, 6-hydroxydecahydroisoquinoline and 7-hydroxy decahydroisoquinoline.

In order to produce the 5, 6, 7 or 8-hydroxy-2-lower alkyldecahydroisoquinolines it appears necessary to first convert the 5, 6, 7or 8-hydroxy-2-lower alkylisoquinolinium halide to the correspondinghydroxide and to then hydrogenate the resulting hydroxide. Production ofthe hydroxide can be readily achieved by reacting the halide with silveroxide. This reaction can be illustrated as follows:

HO HO N n, Agto N m AgX X OH- wherein R is lower alkyl and X is a halideion. The reaction proceeds readily in an aqueous lower alcohol such as50% methanol. The desired product can be isolated from the reactionmixture by conventional procedures. Among the compounds which may beproduced in this way are -hydroxy-2-ethylisoquinolinium hydroxide,5-hydroxy-2- methylisoquinolinium hydroxide,7-hydroxy-2-propylisoquinolinium hydroxide and8-hydroxy-2-ethylisoquinolinium hydroxide.

Conversion of the 5, 6, 7 or 8-hydroxy-2-lower alkyl isoquinoliniumhydroxide to the 5, 6, 7 or 8-hydroxy-2- lower alkyldecahydroisoquinoline can be effected by hydrogenation in glacial aceticacid using a platinum oxide catalyst even though the same conditionslead to the bisether when a halide anion, instead of the hydroxyl anion,is present on the starting material. The process using the hydroxidestarting material can be represented as follows:

HO HO and where R is lower alkyl and R R and R are hydrogen, lower alkylsuch as methyl and ethyl, lower alkoxy such as methoxy and ethoxy, or ahalogen such as chlorine and bromine.

The esters may be produced by reacting the appropriate benzoyl halidewith a hydroxy-Z-lower alkyl-l,2,3,4-tetrahydroisoquinoline or ahydroxy-Z-lower alkyl decahydroisoquinoline. These reactions can berepresented as follows:

wherein X is a reactive halogen, particularly chlorine or bromine and RR R and R have the assigned significance.

The esterification is readily effected in an organic solvent underanhydrous conditions at moderately elevated temperatures and advisablyunder reflux conditions. Dry benzene and toluene are particularlysuitable reaction media. After the reaction is terminated the desiredproduct can be isolated from the reaction mixture by conventionalprocedures. Somewhat higher esterification temperatures are used toesterify the decahydro compounds because the hydroxy group on suchcompounds is less reactive than on the aromatic nucleus present in the1,2,3,4-tetrahydroisoquinolines.

Some of the esters which may be formed as described, using theappropriate reactants, are

5-benzoyloxy-2-ethyl-l,2,3,4-tetrahydroisoquinoline,

S-benzoyloxy-Z-ethyl decahydroisoquinoline,

5- 3,4,5-trimethoxybenzoyloxy) -2-ethyl-1,2,3,4-tetrahydroisoquinoline,

5 3,4,5 -trimethoxybenzoyloxy) -2-ethyl decahydroisoquinoline,

5- 3,4,5-trimethoxybenzoyloxy) -2-methyl decahydroisoquinoline,

5- 3,4,5 -triethoxybenzoyloxy) -2-propyl-1,2,3,4-tetrahydroisoquinoline,

S-(p-chlorobenzoyloxy) -2-ethyl-l,2,3,4-tetrahydroisoquinoline, and

5- (o-methylbenzoyloxy) -2-ethyl decahydroisoquinoline.

Acid addition salts of the bases of this invention are produced bycontacting the compounds with an organic or inorganic acid such ashydrochloric, sulfuric, formic, citric, maleic, succinic and fumaricacids.

Quaternary ammonium salts are formed by contacting the compounds with asuitable alkylating agent such as dimethyl sulfate or an alkyl halidesuch as methyl chloride and ethyl bromide.

The compounds of this invention, being amines, have use as neutralizingagents. In addition, the compounds may be used in the isolation andpurification of penicillin with which they will form salts.

The compounds of this invention also possess biological activity inanimals and thus are potentially useful as drugs. They can be used asbiologically active standards in evaluating other compounds for similaractivity in animals.

A compound of the formulae and N-R a and acidaddition and quaternaryammonium salts thereof, wherein R represents a lower alkyl, R representshydrogen or a lower alkyl, and R represents a benzoyl group of theformula tween compounds, some of the compounds provided herewithelevate, while some lower, blood pressure in animals. In addition, thecompounds generally increase arterial blood flow in animals followingintra-arterial injection except for S-hydroxy Z-ethylisoquinoliniumhalide (bromide) which decreases arterial blood flow. Increased bloodflow would appear desirable in the treatment of peripheral vascular andcerebrovascular insufficiency.

The following data summarizes animal tests with compounds of thisinvention:

(A) S-hydroxy-Z-ethylisoquinolinium bromide (M-2) In mice it has anacute approximate LD of 63-125 mg./kg./i.p.

Following intravenous administration of 5 mg./kg. of M2 to the bilateralvagotomized anesthetized dog, M-2 produced an increase (50-117 mm. Hg)in arterial blood pressure accompanied by a moderate increase in heartrate while essentially no effects were noted on respiratory rate.

M-2 produced slight inhibition of the carotid occlusion pressorresponse.

Intra-arterial administration of M-2 decreased peripheral blood flow inthe anesthetized dog.

M-2 was devoid of antiarrhythmic activity in the mouse(chloroform-induced ventricular fibrillation) assay procedure. However,the antiarrhythmic activity of quinidine, a well-known antiarrhythmicagent, was found to be potentiated by M-Z in this test. This is shown by1 61.8. is quinidine sulfate.

The data show that the ED for quinidine is about 48 when used with M-2.This is much lower than the ED value of 72 obtained when quinidine wasused alone.

(B) S-hydroxy-Z-ethyl-1,2,3,4-tetrahydroisoquinoline HBr (M-3) In miceit has an acute approximate LD of -250 mg./kg./i.p.

Following intravenous administration of 5 mg./kg. of M-3 to thebilateral vagotomized anesthetized dog, it produced a slight increase inblood pressure and heart rate and a moderate increase in respiratoryrate. Central nervous system stimulation was manifested by increasedrate of respiration and lessening of depth of anesthesia with decreasedskeletal muscle relaxation. Intra-arterial administration of M-3increased peripheral blood flow in the anesthetized dog.

The vasodilator properties of M-3, as evidenced by increased bloodvolume flow subsequent to drug administration, were comparable topapaverine when each was administered intra-arterially to theanesthetized dog as shown by the following data:

Blood Pressure Blood E10 (mm. Hg (ca/mm.)

Before After Before After (C)5-(3,4,5-trimethoxybenzoyloxy)-2ethyl-l,2,3,4- tetrahydroisoquinolineHBr (M-6) In mice it has an acute approximate LD of 250-500rng./kg./i.p.

7 At and mg./kg./i.v. of M-6 in bilateral vagotomized anesthetized dogsa rise of blood pressure of 13 to mm. Hg was obtained with little or nochange in heart rate. Intra-arterial administration of M-6 increasedperipheral blood flow in the anesthetized dog.

(D) S-hydroxy-2-ethyldecahydroisoquinoline hydro'bromide (M-7) A dose of10 mg./kg. administered by the intravenous route to the bilateralvagotomized anesthetized dog produced a slight rise (8 to 11 mm. Hg) inarterial blood pressure. Intra-arterial administration of M-7 producedan increase in peripheral blood flow in the anesthetized dog.

(E) Bis- (Z-ethyldecahydroisoquinoline ether dihydrobromide (M7a) BloodPressure Blood Flow (mm. Hg) (co/min.)

Dose, rng. Before After Before After Papaverine 0. 1 130 126 5 23 0.1139 135 7 41 Papaverme. 0. 3 123 119 10 51 0.15 125 123 12 62 (F)5-(3,4,5-trimethoxybenzoyloxy)2-ethyldecahydrois0- quinolinehydrobromide (M-8) A dose of 1 to 5 mg./kg. administered by theintramany years and was therefore used as the standard of comparison.M-8 compares favorably with quinidine. Although M-8 is more potent, itis also more toxic and as a result the two compounds appear to possess anear comparable safety factor. The term, safety factor, is the ration ofthe toxic dose to the effective dose.

M-8 and quinidine were studied for antiarrhythmic activity in dogs withventricular arrhythmia produced experimentally by interrupting bloodfiow to the myocardium. In this test, animals are prepared by openingthe thorax and ligating the anterior descending branch of the leftcoronary artery. Test compounds are then evaluated for antiarrhythmicactivity on the first postoperative day when he animal is in theunanesthetized state.

Two groups of dogs consisting of 6 animals per group were surgicallyprepared as described. Group [received 10 mg./kg. of quinidine sulfateand Group II received 2 mg./l g. of Compound M-8. Each compound wasadministered intravenously over a two minute period while recording theelectrocardiogram and femoral arterial blood pressure. In addition, eachanimal was observed for gross symptoms of toxicity both during andsubsequent to administration of the compounds. Measurements of theelectrocardiogram and blood pressure were taken during time of drugadministration and at 1, 5, 10, 20, 30 and minutes thereafter.Comparative drug effects were obtained by calculating the mean andstandard error of change in ventricular rate, ectopic rate and bloodpressure. It is to be noted that there was no significant difference (P0.05) between the mean control values for each group prior to drugadministration. Results of calculations showed that both compoundsslowed ventricular rate and decreased ectopic ventricular rate and thatthere was no significant difference between the effects of the twocompounds. It was further noted that peak activity time and duration ofactivity of M-8, within the limits of the experimental period, comparedfavorably with that of quinidine. These data are given in the followingTables I and II.

TABLE I.EFFECT OF QUINIDINE SULFATE AND M-8 ON TOTAL VENTRICULAR RATE INCORONARY DOG FOLLOWING INTRAVENOUS ADMINISTRATION [Total VentricularRate (m1nutes)] Compound: Quiri ildine sulfate l MeaniStandard Error.

TABLE IL-EFFECT OF QUINIDINE SULFATE AND M-8 ON VENTRICULAR ECTOPIC RATEIN CORONARY DOG FOLLOWING INTRAVENOUS ADMINISTRATION [VentricularEctopic Rate (mlnutes)] Dose, -l -l I.V. Control 1 min. 5 min. 10 min.20 mm. 30 min. 40 min.

Compound:

Quinidine sulfate. 10 169:};21 92:1;31 90=i=33 1125;30 1025136 1023:331205:24 M-8 2 153:1:14 34119 93:1:25 86:1:29 118:1:19 1155;25 128:1:17

venous route to the bilateral vagotomized anesthetized dog produced aslight to moderate (10 to 37 mm. Hg) de crease in arterial bloodpressure. Intra-arterial administration of M-8 produced an increase inperipheral blood flow in the anesthetized dog.

Compound M-8 has been found to possess antiarrhythmic activity. Thisindicates potential usefulness in the treatment and/or prophylaxis ofcardiac arrhythmias. Quinidine has been used successfully in thetreatment of certain types of abnormal rhythm of the human heart for Thecomparative effect of the two compounds on blood pressure are given inthe following Table III where it may be noted that near comparablechanges were produced in each group at one minute after dosing, at whichtime the blood pressure was elevated subsequent to M8 administration andwas lowered subsequent to quinidine administration. It should further benoted that qualitative signs of gross toxicity were essentiallycomparable in each group while quantitative differences in toxicsymptoms were not readily apparent.

TABLE Ill-EFFECT OF QUINIDINE SULFATE AND M-8 ON ARTERIAL BLOOD PRESSUREIN CO RONARY D O G FOLLOWIN G INT RAVENOUS ADMINISTRATION [Mean BloodPressure (mm. Hg)] Dose, me/ke/ LV. Control 1 mln. mm. min. mm. min. mm.

Compound:

Quinidine sulfate 10 76:1;5 645:8 73:1;8 66;};7 72:1;8 66=b8 66=l=9 M-82 893:5 95=|=4 86:1;6 89i6 855:5 84=|=5 84i4 The oral absorption ofquinidine sulfate and M-8 was studied in eight additional dogs whichwere similarly prepared by surgical treatment. Three animals served ascontrols and received 5 mL/kg. of 0.9% NaC-l, two received 2O mg./kg. ofquinidine sulfate and the remaining three received 8 mg./kg. of M8. Thecompounds were dissolved in 0.9% NaCl and administered with the aid of astomach tube. Electrocardiogram measurements were recorded (Table IV)and each dog was observed for signs of gross toxicity. Overt toxic signswere not observed in these animals and the effect of the diflierenttreatments on ectopic rate is given in the following Table V.

A typical tablet can have the composition:

The oral route of administration is preferred. However, other routes,such as by injection, can be employed when warranted.

TABLE IV.TO'IAL VENTRICULAR RATE (MINUTES) Comparative toxicity studiesusing quinidine sulfate and M-8 were conducted in twelve additionalunanesthetized dogs which had not previously received any form oftreatment. |Six dogs received 20 mg./kg. of quinidine sulfate and sixreceived 4 mg./kg. of M-8. At these dose levels, no difference betweenthe compounds was readily apparent in either the nature or severity oftoxic signs.

The active agents of this invention can be administered to animals aspure compounds. It is advisable, however, to first combine one or moreof the compounds with a suitable pharmaceutical carrier to attain a moresatisfactory size to dosage relationship.

Pharmaceutical carriers which are liquid or solid can be used. Solidcarriers such as starch, sugar, talc and the like can be used to formpowders. The powders can be used for direct administration or they maybe used to make tablets or fill gelatin capsules. Suitable lubricantslike magnesium stearate, binders such as acacia and gelatin, anddisintegrating agents like sodium carbonate in combination with citricacid, or methylcellulose or starch separately, can be used to formtablets.

Unit dosage forms such as tablets and capsules can contain any suitablepredetermined amount of one or more of the active agents, and may beadministered one or more at a time at regular intervals. Such unitdosage compositions can contain, for example, from about 0.02 to 500 mg.of active agent. However, about 20 mg. is consideredthe highest amountwhich is needed for the active compounds in the unit dosages. Such unitdosage forms, however, should generally contain a concentration of 0.1%to 50% by weight of one or more of the active compounds.

The following examples are presented to illustrate the preparation ofcompounds within the scope of this invention.

EXAMPLE 1 5-hydroxy-2-ethylisoquinolinium bromide Forty grams (0.28mole) of S-hydroxyquinoline was dissolved in ml. of absolute ethanol andrefluxed for 8 hours on a steam bath with 50% excess ethyl bromide (40g.) (0.37 mole). The ethanol and excess ethyl bromide was thenevaporated off and the resulting brown solid recrystallized from ethanolto yield 57.47 g. (82%) of light brown needles, M.P. 209.4210.6 C.

Analysis.Calcd. for C H NOBr: C, 51.97; H, 4.73; N, 5.51; Br, 31.50.Found: C, 51.77; H, 4.68; N, 5.13; Br, 31.50.

EXAMPLE 2 S-hydroxy-Z-ethyl-1,2,3,4-tetrahydroisoquinoline hydrobromide224.6 C. The ultraviolet spectrum of this compound had A 272 and 277 m(log 3.24 and 3.23, respectively). Analysis.Calcd. for C H NOBr: C,51.17; H, 6.20; N, 5.43; Br, 31.01. Found: C, 51.17; H, 6.06; N, 5.42;Br, 31.28.

EXAMPLE 3 5-(3,4,S-trimethoxybenzoyloxy)-2-ethyl-1,2,3,4-tetrahydroisoquinoline hydrobromide Four and three-tenths grams (0.0166mole) of 5-hydroxy-2-ethyl 1,2,3,4 tetrahydroisoquinoline hydrobromidewas dissolved in 100 ml. of water and sodium hydroxide solution addeduntil no further precipitation was evident. The resulting suspension wasextracted with ether, dried, and the solvent removed to yield 3.0 g.(100%) of white solid. This base was dissolved in 100 ml. of dry benzeneand added to a solution of 4.0 g. (0.0173 mole) of3,4,5-trimethoxybenzoyl chloride in 100 ml. of dry benzene. Two grams ofdry sodium bicarbonate was added to this mixture and the whole refluxedfor 8 hours on a steam bath. The gelatinous precipitate which separatedout was filtered (3.3 g.) and the filtrate extracted with dilutehydrochloric acid. This acid extract, made alkaline with sodiumhydroxide, was extracted with ether and dried. The ether was removed toyield 3.6 g. of a pale yellow oil. The hydrobromide salt of this basewas recrystallized from ethanol-ether to yield 3.7 g. (32.3%) as shortwhite needles, M.P. 213.2- 213.4 C.

AnaIysis.--Calcd. for C H NO Br: C, 55.75; H, 5.75; N, 3.10; Br, 17.70.Found: C, 55.59; H, 5.71; N, 3.18; Br, 17.80.

EXAMPLE 4 5-hydroxydecahydroisoquinoline and hydrochloride Five grams ofS-hydroxyisoquinoline was dissolved in 50 ml. of glacial acetic acid and0.5 ml. of concentrated sulfuric acid added. The resulting solution washydrogenated over 5 g. of Adams platinum oxide at 50 lbs. per sq. in.pressure for 36 hours at room temperature. The exhausted catalyst wasfiltered from the hydrogenated solution and the filtrate diluted withapproximately 50 ml. of water, made alkaline by the addition of sodiumhydroxide pellets, and extracted with ether. The dried ethereal extractwas evaporated carefully to yield a yellow oily residue (2.7 g.) whichwas treated with dry hydrogen chloride in ether to yield 2.9 g. (51%) ofthe base hydrochloride, recrystallized from ethanol-ether, M.P.1910-1930 C. The ultraviolet spectrum of this compound was taken inwater and showed no absorption throughout the range 220-340 mAnalysis.Calcd. for C H NOCl: C, 56.25; H, 9.38; N, 7.29; Cl, 18.75.Found: C, 56.33; H, 9.43; N, 7.22; CI, 18.80.

EXAMPLE 5 5 -hydroxy-2-ethyldecahydroisoquinoline and hydrobromide Eightgrams (0.031 mole) of 5-hydroxy-2-ethylisoquinolinium bromide wastreated with moist silver oxide, prepared from the action of sodiumhydroxide on silver nitrate (13 g.), in 100 ml. of a 50% aqueousmethanol solution for 24 hours. The silver bromide formed was thenfiltered from the solution using celite/charcoal mixture as a filteraid. The solvent was evaporated off under reduced pressure at as low atemperature as possible to yield 5.7 g. (96%) of5-hydroxy-2-ethylisoquinolinium hydroxide. This compound washydrogenated as described in Example 4. The resulting5-hydroxy-2-ethyldecahydroisoquinoline was converted to the hydrobromide5.62 g. (81%), which was recrystallized from ethanol-ether to yield finewhite needles, M.P. 218.4- 219.0 C. The ultraviolet spectrum of thiscompound indicated no absorption in the range 220-310 m Analysis.Calcd.for C H NOBr: C, 50.00; H, 8.33;

12 N, 5.30; Br, 30.31. Found: C, 49.80; H, 8.31; N, 5.52;

EXAMPLE 6 5-(3,4,5-trimethoxybenzoyloxy)-2-ethy1decahydroisoquinolineand hydrobromide Five grams (0.027 mole) of5-hydroxy-2-ethyldecahydroisoquinoline was dissolved in 20 ml. of sodiumdried toluene and added to a solution of 15 g. (0.065 mole) of3,4,5-trimetlr 'oxybenzoyl chloride and refluxed for 48 hours. Theresulting suspension was filtered and the toluene filtrate extractedwith dilute hydrochloric acid. Neutralization of this acid extract wasfollowed by extraction with ether. The ether extract was dried andevaporated to yield a brown viscous oil. This was purified bychromatography on a Florosil column and eluted with petroleum ether(60-90 C.) ether (10:1). Large prisms separated from the fractions onstanding overnight. This material was crystallized from petroleum ether(30-60 C.) to yield 4.52 g. (52%) of large prisms, M.P. 99.8- 100.3 C.

Analysis.Calcd. for C H NO C, 66.82; H, 8.28; N, 3.71. Found: C, 67.06;H, 8.32; N, 3.64.

One gram of the base was converted to the hydrobromide andrecrystallized from ethanol-ether to yield 1.06 g. (88%) of short whiteneedles, M.P. 197.8- 198.6 C.

Analysis.Calcd. for C H NO Br: C, 55.02; H, 7.04; N, 3.06; Br, 17.43.Found: C, 55.12; H, 7.15; N, 3.11;

EXAMPLE 7 Bis-(2-ethyldecahydroisoquinoline ether Five grams of5-hydroxy-2-ethylisoquinolinium bromide was dissolved in 50 ml. ofglacial acetic acid with the aid of gentle heating on a steam bath.Five-tenths ml. of concentrated sulfuric acid was added and the mixturehydrogenated over 5 g. of Adams platinum oxide at 50 lbs. per sq. in.pressure for a period of 36 hours at room temperature. The exhaustedcatalyst was filtered, the acidic filtrate diluted with water and madestrongly alkaline by the addition of sodium hydroxide solution. The basewas then extracted with ether and converted to the hydrobromide salt.Upon recrystallization from ethanol-ether, 2.14 g. (42%) of fine whiteneedles were obtained, melting at 196.6-197.1 C. The ultravioletspectrum of this compound showed no absorption through the range 220-310Ill .L. The infrared spectrum (KBr) showed a medium absorption band at1,110 cm.- in accordance with the absorption reported for an etherlinkage in L. J. Bellamy, The Infrared Spectra of Com plex Molecules,Wiley and Sons, New York, 1958, p. 115.

Analysis.Calcd. for C H N OBr: C, 52.52; H, 8.29; N, 5.49; Br, 31.31.Found: C, 52.57; H, 8.48; N, 5.41; Br, 31.20.

EXAMPLE 8 Diethiodide of Bis-(2-ethyldecahydroisoquinoline)ether Thediethiodide derivative of the basic ether of Example 7 was prepared byrefiuxing the free base, obtained from the neutralization of 1.0 g. ofbis-(Z-ethyldecahydroisoquinoline)ether dihydrobromide, dissolved in 25ml. of dry benzene, for 4 hours with excess ethyl iodide. Theprecipitated quaternary iodide was filtered and recrystallized from analcohol-ether mixture to ield 0.93 g. (72%) of fine white needles, M.P.245.0-245.4 C. The infrared spectrum (KBr) showed a medium intensityabsorption band at 1110 cmr Analysis.-Calcd. for C H N Ol C, 47.28; H,7.63; N, 4.24; I, 38.43. Found: C, 47.28; H, 7.40; N, 4.27; I, 38.20.

What is claimed is:

1. The method of inducing antiarrhythmic activity which comprisesadministering about 0.02 to 500 mg.

of 5-(3,4,S-trimethoxybenzoyloxy) -2-lower alkyl decahydroisoquinoline,or a nontoxic acid addition salt thereof, to an animal.

2. The method of inducing antiarrhythmic activity which comprisesadministering about 0.02 to 500 mg. of 5(3,4,S-trimethoxybenzoyloxy) 2ethyl decahydroisoisoquinoline, or a nontoxic acid addition saltthereof, an animal.

3. The method of inducing antiarrhythmic activity which comprisesadministering about 0.02 to 500 mg. of5-(3,4,S-trimethoxybenzoyloxy)-2-methyl decahydroisoquinoline, or anontoxic acid addition salt thereof, of an aminal.

4. A pharmaceutical composition comprising about 0.02 to 500 mg. of5-(3,4,S-trimethoxybenzoyloxy)-2- lower alkyl decahydroisoquinoline, ora nontoxic acid addition salt thereof, admixed with a pharmaceuticalcarner.

5. A pharmaceutical composition comprising about 14 0.02 to 500 mg. of5-(3,4,S-trimethoxybenzoyloxy)-2- ethyl decahydroisoquinoline, or anontoxic acid addition salt thereof, admixed with a pharmaceuticalcarrier.

6. A pharmaceutical composition comprising about 0.02 to 500 mg. of5-(3,4,S-trimethoxybenzoyloxy)-2- methyl decahydroisoquinoline, or anontoxic acid addition salt thereof, admixed with a pharmaceuticalcarrier.

References Cited UNITED STATES PATENTS 6/1954 Cusic 260287 5/1967Umezawa et a1. 260287 OTHER REFERENCES FRANK CACCIAPAGLIA, 111., PrimaryExaminer UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No3 ,475 ,538 October 28 1969 Ian William Mathison It is certified thaterror appears in the above identified patent and that said LettersPatent are hereby corrected as shown below:

' Column 3, line 60, the formula 0 3 H should read 2 C-X Column 7 line19 "+5" should read 5 Column 8 line 14 "he" should read the Column 10line 14 "trimeth oxybenzoloxy" should read trimethoxybenzoyloxy Column13 line 8 before "an animal" insert to line 12 "of" should read to line13 "aminal" should read animal Signed and sealed this 26th day of May1970 (SEAL) Attest:

EDWARD M.FLETCHER,JR. WILLIAM E. SCHUYLER, JR. Attesting OfficerCommissioner of Patents

